Aminothaizoles and their use as adenosine receptor antagonists

ABSTRACT

Compounds of formula (I) in free or salt form, where A is a C 6 -C 15  monovalent aromatic group. R 1  is hydrogen, phenyl optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkoxy-C 1 -C 8 -alkyl or acyloxy, or a 5- or 6-membered monovalent heterocyclic group, R 2  is hydrogen, C 1 -C 8 -alkyl, acyl or CON(R 3 )R 4 , provided that R 2  is C 1 -C 8 -alkyl, acyl or CON(R 3 )R 4  when R 1  is hydrogen, R 3  and R 4  are each independently hydrogen, or C 1 -C 8 -alkyl, together with the nitrogen atom to which they are attached denote a 5- or 6-membered heterocyclic group, and Z l , Z 2 , Z 3  and Z 4  are each independently N or CR 5 , at least one of them being CR 5 , and R 5  is hydrogen, C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy. The compounds are useful as adenosine receptor antagonists, particularly in the treatment of inflammatory or obstrucive airways diseases.

[0001] This invention relates to organic compounds, their preparationand their use as pharmaceuticals.

[0002] In one aspect, the present invention provides compounds offormula

[0003] in free or salt form, where

[0004] Ar is a C₆-C₁₅ monovalent aromatic group,

[0005] R¹ is hydrogen, phenyl optionally substituted by one or moresubstituents selected from halogen, cyano, hydroxy, C₁-C₈-alkyl,C₁-C₈-haloalkyl, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl or acyloxy, or a5- or 6-membered monovalent heterocyclic group

[0006] R² is hydrogen, C₁-C₈-alkyl, acyl or —CON(R³)R⁴, provided that R²is C₁-C₈-alkyl, acyl or —CON(R³)R⁴ when R¹ is hydrogen,

[0007] R³ and R⁴ are each independently hydrogen or C₁-C₈-alkyl, ortogether with the nitrogen atom to which they are attached denote a 5-or 6-membered heterocyclic group,

[0008] Z¹, Z², Z³ and Z⁴ are each independently N or CR⁵, at least oneof them being CR⁵, and

[0009] R⁵ is hydrogen, C₁-C₈-alkyl or C₁-C₈-alkoxy.

[0010] Terms used in the specification have the following meanings:

[0011] “C₁-C₈-alkyl” as used herein denotes straight chain or branchedC₁-C₈-alkyl, which may be, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight orbranched pentyl, straight or branched hexyl, straight or branchedheptyl, or straight or branched octyl. Preferably, C₁-C₈-alkyl isC₁-C₄-alkyl.

[0012] “C₁-C₈-alkoxy” as used herein denotes straight chain or branchedC₁-C₈-alkoxy which may be, for example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight orbranched pentoxy, straight or branched hexyloxy, straight or branchedheptyloxy, or straight or branched octyloxy. Preferably, C₁-C₈-alkoxy isC₁-C₄-alkoxy.

[0013] “C₁-C₈-haloalkyl” as used herein denotes C₁-C₈-alkyl ashereinbefore defined substituted by one or more halogen atoms,preferably one, two or three halogen atoms, preferably fluorine orchlorine atoms. Preferably C₁-C₈-haloalkyl is C₁-C₄-alkyl substituted byone, two or three fluorine or chlorine atoms.

[0014] “C₁-C₈-alkoxy-C₁-C₈-alkyl” as used herein denotes C₁-C₈-alkyl ashereinbefore defined substituted by C₁-C₈-alkoxy as hereinbeforedefined.

[0015] “C₁-C₈-alkoxy-C₁-C₈-alkoxy” as used herein denotes C₁-C₈-alkoxyas hereinbefore defined substituted by C₁-C₈-alkoxy as hereinbeforedefined. “C₁-C₈-alkylcarbonyl”, “C₁-C₈-haloalkylcarbonyl” and“C₁-C₈-alkoxycarbonyl” as used herein denote C₁-C₈-alkyl,C₁-C₈-haloalkyl or C₁-C₈-alkoxy respectively as hereinbefore definedattached by a carbon atom to a carbonyl group.

[0016] “Acyl” as used herein denotes alkylcarbonyl, for exampleC₁-C₈-alkylcarbonyl where C₁-C₈-alkyl may be one of the C₁-C₈-alkylgroups hereinbefore mentioned, optionally substituted by one or morehalogen atoms; cycloalkylcarbonyl, for example C3-C₈-cycloalkylcarbonylwhere C₃-C₈-cycloalkyl may be, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; 5- or 6-memberedheterocyclylcarbonyl having one or more, preferably one or two, heteroatoms selected from nitrogen, oxygen and sulfur in the ring, such asfurylcarbonyl, methylthienylcarbonyl or pyridylcarbonyl; arylcarbonyl,for example C₆-C₁₀-arylcarbonyl such as benzoyl; or aralkylcarbonyl, forexample C₆ to C₁₀-aryl-C₁-C₄-alkylcarbonyl such as benzylcarbonyl orphenylethylcarbonyl.

[0017] “Acyloxy” as used herein denotes alkylcarbonyloxy, for exampleC₁-C₈-alkylcarbonyloxy where C₁-C₈-alkyl may be one of the C₁-C₈-alkylgroups hereinbefore mentioned, optionally substituted by one or morehalogen atoms; cycloalkylcarbonyloxy, for exampleC₃-C₈-cycloalkylcarbonyloxy where C₃-C₈-cycloalkyl may be, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orcyclooctyl; 5- or 6-membered heterocyclylcarbonyloxy having one or twohetero atoms selected from nitrogen, oxygen and sulfur in the ring, suchas furylcarbonyloxy or pyridylcarbonyloxy; arylcarbonyloxy, for exampleC₆-C₁₀-arylcarbonyloxy such as benzoyloxy; or aralkylcarbonyloxy, forexample C₆ to C₁₀-aryl-C₁-C₄-alkylcarbonyloxy such as benzylcarbonyloxyor phenylethylcarbonyloxy. Preferably acyloxy is C₁-C₄-alkylcarbonyloxy.

[0018] “Halogen” as used herein may be fluorine, chlorine, bromine oriodine; preferably it is fluorine or chlorine.

[0019] Ar may be, for example, phenyl optionally substituted by one ormore substituents, for example, one, two or three substituents selectedfrom halogen, cyano, C₁-C₈-alkyl or C₁-C₈-haloalkyl, or Ar may benaphthyl. Ar is preferably phenyl optionally substituted by halogen,cyano or C₁-C₈-alkyl, preferably meta or para to the indicated thiazolering.

[0020] R¹ may be, for example, hydrogen, phenyl optionally substitutedby halogen, cyano, hydroxy, C₁-C₈-alkyl, C₁-C₈-haloalkyl, C₁-C₈-alkoxy,C₁-C₈-alkoxy-C₁-C₈-alkyl, carboxy, C₁-C₈-alkoxycarbonyl orC₁-C₈-alkylcarbonyloxy, or a monovalent 5- or 6-membered heterocyclicgroup having one, two or three ring hetero atoms selected from nitrogen,oxygen and sulfur, such as pyrrolyl, triazolyl, pyridyl, oxopyridyl,piperidyl, pyridazinyl, pyrimidinyl, pyrazinyi, pyrazoiyl, pyrazoilnyi,piperazinyi, morpholinyi, turyl, pyranyl, thienyl or thiazolyl,optionally substituted by one or more substituents selected fromC₁-C₈-alkyl, hydroxy, C₁-C₈-alkoxy or C₁-C₈-alkoxy-C₁-C₈-alkoxy.Preferably R¹ is hydrogen, phenyl optionally substituted by cyano orC₁-C₄-alkoxy, or a monovalent 6-membered N-heterocyclic group,preferably a heteroaromatic group, especially pyridyl,C₁-C₄-alkylpyridyl, di(C₁-C₄-alkyl)pyridyl, C₁-C₄-alkoxypyridyl,pyrazinyl, C₁-C₄-alkylpyrazinyl, C₁-C₄-alkoxypyrazinyl orC₁-C₄-alkoxy-C₁-C₄-alkoxypyrazinyl.

[0021] R² may be, for example, hydrogen, C₁-C₈-alkyl, formyl,C₁-C₈-alkylcarbonyl, C₁-C₈-haloalkylcarbonyl, C₃-C₈-cycloalkylcarbonyl,phenylcarbonyl in which the phenyl moiety is optionally substituted byhalogen, cyano, hydroxy, C₁-C₈-alkyl or C₁-C₈-alkoxy,heterocyclylcarbonyl in which the heterocyclyl group is 5- or 6-memberedand has one or more, preferably one or two, ring hetero atoms selectedfrom nitrogen, oxygen and sulfur, or a group —CON(R³)R⁴. Preferably R²is hydrogen, C₁-C₄-alkylcarbonyl, C₃-C₆-cycloalkylcarbonyl,phenylcarbonyl where the phenyl group is optionally substituted byC₁-C₈-alkoxy, or heterocyclylcarbonyl in which the heterocyclyl group is5- or 6-membered and has a ring hetero atom selected from nitrogen,oxygen and sulfur, such as furylcarbonyl, tetrahydrofirylcarbonyl,C₁-C₄-alkylfurylcarbonyl, thienylcarbonyl, C₁-C₄-alkyl-thienylcarbonyl,N-(C₁-C₄-alkyl)pyrrolylcarbonyl and pyridylcarbonyl.

[0022] Where present, R³ and R⁴ may each independently be, for example,hydrogen or C₁-C₄-alkyl, or together with the nitrogen atom to which theare attached may denote a 5-membered heterocyclyl group such as pyrrolylor pyrrolidinyl or a 6-membered heterocyclyl group such as pyridyl,piperidyl, piperazinyl or morpholinyl. Preferably R³ and R⁴, wherepresent, are each C₁-C₈-alkyl, especially methyl, or together with thenitrogen atom to which they are attached denote a 6-memberedheterocyclyl group, especially pyridyl.

[0023] When two or more of Z¹, Z², Z³ and Z⁴ denote CR⁵, the CRS groupsmay be the same or different. Preferably R⁵ is hydrogen or C₁-C₄-alkyl.Preferably Z¹ and Z³ each denote N and Z² and Z⁴ each independentlydenote CR⁵, or Z² denotes N and Z¹, Z³ and Z⁴ each independently denoteCR⁵ where R⁵ is hydrogen or C₁-C₄-alkyl. In especially preferredembodiments, Z¹ and Z³ each denote N and Z² and Z⁴ each denote CH, or Z¹denotes CR⁵ where R⁵ is hydrogen or C₁-C₄-alkyl, Z² denotes N and Z³ andZ⁴ each denote CH.

[0024] Preferred compounds of formula I in free or salt form are thosewhere

[0025] Ar is phenyl optionally substituted by halogen or cyano,

[0026] R¹ is hydrogen, phenyl optionally substituted by cyano orC₁-C₄-alkoxy, or a monovalent 6-membered N-heterocyclic group,

[0027] R² is hydrogen, C₁-C₄-alkylcarbonyl, C₃-C₆-cycloalkylcarbonyl,phenylcarbonyl where the phenyl group is optionally substituted byC₁-C₄-alkoxy, or heterocyclylcarbonyl where the heterocyclyl group is 5-or 6-membered and has one or two ring hetero atoms selected fromnitrogen, oxygen and sulfur, and

[0028] either Z¹ and Z³ each denote N and Z² and Z⁴ each denote CH, orZ¹ denotes CR⁵ where R⁵ is hydrogen or C₁-C₄-alkyl, Z₂ denotes N and Z³and Z⁴ each denote CH.

[0029] Further preferred compounds of formula I in free or salt form arethose where

[0030] Ar is phenyl substituted by halogen or cyano meta or para to theindicated thiazole ring,

[0031] R¹ is a monovalent 6-membered N-heterocyclic group,

[0032] R² is hydrogen and

[0033] either Z¹ and Z³ each denote N and Z² and Z⁴ each denote CH, orZ¹ denotes CR⁵ where R⁵ is hydrogen or C₁-C₄-alkyl, Z₂ denotes N and Z³and Z⁴ each denote CH.

[0034] Other further preferred compounds of formula I in free or saltform are those where

[0035] Ar is phenyl substituted by halogen or cyano meta or para to theindicated thiazole ring,

[0036] R¹ is hydrogen,

[0037] R² is phenylcarbonyl where phenyl is optionally substituted byC₁-C₄-alkoxy, or heterocyclylcarbonyl where the heterocyclyl group is 5-or 6-membered and has a ring hetero atom selected from oxygen andsulfur, and

[0038] either Z¹ and Z³ each denote N and Z² and Z⁴ each denote CH, orZ¹ denotes CR⁵ where R⁵ is hydrogen or C₁-C₄-alkyl, Z₂ denotes N and Z³and Z⁴ each denote CH.

[0039] Especially preferred specific compounds of formula I are thosedescribed hereinafter in the Examples.

[0040] The compounds represented by formula I are capable of formingacid addition salts, particularly pharmaceutically acceptable acidaddition salts. Pharmaceutically acceptable acid addition salts of thecompound of formula I include those of inorganic acids, for example,hydrohalic acids such as hydrofluoric acid, hydrochloric acid,hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid,phosphoric acid; and organic acids, for example aliphatic monocarboxylicacids such as formic acid, acetic acid, trifluoroacetic acid, propioncacid and butyric acid, aliphatic hydroxy acids such as iactic acid,citric acid, tartaric acid or malic acid, dicarboxylic acids such asmaleic acid or succinic acid, aromatic carboxylic acids such as benzoicacid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid,aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoicacid, 1-hydroxynaphthalene-2-carboxylic acid or3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such asmethanesulfonic acid or benzenesulfonic acid. These salts may beprepared from compounds of formula I by known salt-forming procedures.

[0041] Compounds of formula I which contain acidic, e.g. carboxyl,groups, are also capable of forming salts with bases, in particularpharmaceutically acceptable bases such as those well known in the art;suitable such salts include metal salts, particularly alkali metal oralkaline earth metal salts such as sodium, potassium, magnesium orcalcium salts, or salts with ammonia or pharmaceutically acceptableorganic amines or heterocyclic bases such as ethanolamines, benzylaminesor pyridine. These salts may be prepared from compounds of formula I byknown salt-forming procedures.

[0042] The invention provides, in another aspect, a method of preparinga compound of formula I in free or salt form which comprises

[0043] (i) (A) for the preparation of compounds of formula I where R¹ isoptionally substituted phenyl or a 5- or 6-membered heterocyclic group,reacting a compound of formula

[0044]  in the form of a salt, e.g. a hydrohalide salt thereof, whereAr, Z¹, Z², Z³ and Z⁴ are as hereinbefore defined and X is halogen,preferably bromine or iodine, with a compound of formula

[0045]  where R¹ is phenyl optionally substituted by one or moresubstituents selected from halogen, cyano, hydroxy, C₁-C₈-alkyl,C₁-C₈-haloalkyl, C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl and acyloxy orR² is a 5- or 6-membered monovalent heterocyclic group, and R² is H orC₁-C₈-alkyl or

[0046] (B) for the preparation of compounds of Formula I where R¹ isoptionally substituted phenyl or a 5- or 6-membered heterocyclic group,reacting a compound of formula

[0047]  where Ar, R¹, R² and X are as hereinbefore defined, with acompound of formula

[0048]  where Z¹, Z², Z³ and Z⁴ are as hereinbefore defined or

[0049] (C) for the preparation of compounds of formula I where R¹ isacyl or —CON(R³)R⁴, reacting a compound of formula

[0050]  where Ar, R¹, Z¹, Z², Z³ and Z⁴ are as hereinbefore definedwith, respectively, an acylating derivative of a carboxylic acid, forexample the anhydride or acid chloride thereof, or with a compound offormula C₁-CON(R³)R⁴) where R³ and R⁴ are as hereinbefore defined, and

[0051] (ii) recovering the resultant compound of formula I in free orsalt form.

[0052] Process variant (A) may be carried out in an organic solvent, forexample an alcohol such as ethanol, or a tertiary base such as pyridine.Suitable reaction temperatures are elevated temperatures, for examplefrom 50° C. to reflux temperature of the solvent.

[0053] Process variant (B) may be carried out using known procedures,for example by heating the reactants, optionally in an inert solvent.Suitable reaction temperatures are, for example, from 80 to 160° C.

[0054] Process variant (C) may be carried out using known procedures forreaction of amines with acylating agents.

[0055] Compounds of formula II may be prepared by reacting a compound offormula

[0056] where Ar, Z¹, Z², Z³ and Z⁴ are as hereinbefore defined, withhalogen X₂, preferably bromine. This halogenation may be effected usingknown procedures for alpha halogenation of ketones or analogously, forexample as hereinafter described in the Examples. This reaction may becarried out in situ in the presence of the compound of formula III withwhich the compound of formula II is to be reacted to form a compound offormula I.

[0057] Compounds of formula III are thioureas which are either known ormay be obtained by known procedures. For example they may be prepared byreaction of a compound of formula

[0058] where R¹ and R² are as hereinbefore defined, with benzoylisothiocyanate and hydrolysing the resulting product, for example withaqueous NaOH, to replace the benzoyl group by halogen. The reaction withbenzoyl isothiocyanate may be carried out in an organic solvent, forexample an alcohol such as ethanol. Suitable reaction temperatures arefrom room temperature to reflux temperature of the solvent, conveniently3545° C. The hydrolysis may be effected at elevated temperature, forexample 70° C. to reflux temperature, conveniently at refluxtemperature.

[0059] Compounds of formula IV may be prepared by reacting a compound offormula

[0060] where Ar and X are as hereinbefore defined with a compound offormula III, for example using known procedures such as thosehereinbefore described for reactions of compounds of formulae II andIII, and brominating the resulting aminothiazole, for example usingknown procedures or variants thereof, e.g. as hereinafter described inthe Examples.

[0061] Compounds of formula V are known compounds which are commerciallyavailable or may be prepared by known procedures. Compounds of formulaVI may be prepared by process variant (A) or (B) as described above.Compounds of formula VII may be prepared by reaction of a compound orformula IX with the sodium derivative of a compound of formula V, e.g.using a known procedure such as described hereinafter in the Examples.Compounds of fomulae VIII and IX are known or may be obtained by knownprocedures such as described hereinafter in the Examples.

[0062] Compounds of formula I and their pharmaceutically acceptablesalts are useful as pharmaceuticals. In particular, they exhibitinhibition of adenosine A2b receptor activation, i.e. they act as A2breceptor antagonists. Moreover, in general they selectively inhibitactivation of A2b receptor over the adenosine A1 and A2a receptors.Their inhibitory properties may be demonstrated in the following testprocedures:

[0063] Adenosine A2b Receptor Reporter Gene Assay

[0064] a) Culturing of Chinese Hamster Ovary (CHO) A2b Cell Line

[0065] CHO cells transfected with a Luciferase-expressing reporterplasmid (pCRE-LUCI) and with a plasmid carrying the human adenosine A2breceptor structural gene (pA2bRCV) are routinely cultured in Sulbecco'sModified Eagle Medium (SMEM)—supplemented with 10% v/v fetal calf serum(FCS), 2 mM L-glutamine, 0.4 mg/ml L-proline, 1 nM sodium selenite, 0.5mg/ml Hygromycin B and 1 mg/ml Geneticin—at 37° C., 5% CO₂ and 100%humidity. The cells are left to grow to confluence for 4-5 days. Thecells obtained are passaged using trypsin/EDTA and split at a ratio of 1in 5.

[0066] b) Preparation of Cells for Assay

[0067] Prior to the assay, the CHO-A2b cells are plated onto white96-well View Plate tissue culture plates (Packard) at a density of50,000 cells per well in 50 W of DMEM, and the plates are incubated at37° C., 5% CO₂ and 100% humidity.

[0068] c) Preparation of Reference and Test Compounds

[0069] 10 mM solutions of the reference compound, Xanthine Amine Cogener(XAC), and the test compound in dimethyl sulfoxide (DMSO) are prepared.The solutions are further diluted with DMSO to 100 μM, then diluted to10 μM, and finally to 250 nM or 2.5 μM with Assay Buffer (DMEM PhenolRed-free tissue culture media supplemented with 10 μM Rolipram and 10U/ml adenosine deaminase (ADA). The resulting solutions (40 μl) areadded to the cells in the appropriate wells, the final concentration perwell being 100 nM or 1 μM, and the plates are incubated at 37° C., 5%CO₂ and 100% humidity.

[0070] d) Luciferase Reporter Gene Assay

[0071] 5′-N-ethylcarboxamidoadenosine (NECA), an adenosine A2b agonist,is prepared as a 10 nM solution in DMSO and then diluted to 100 μM withAssay Buffer. This solution is serially diluted in Assay Buffer to givea series of 10 NECA concentrations from 100 to 0.01 μM. 10 μl portionsof the resulting NECA solutions are added to the mixtures of CHO-A2bcells and reference or test compound solutions prepared as describedabove (preincubated for 30 minutes), final concentrations ranging from10 to 0.0005 μM per well. The cells are incubated at 37° C., 5% CO₂ and100% humidity for 3 hours to induce release of cAMP, which then binds tocAMP binding protein (CBP) and the resulting complex interacts with thereporter plasmid to express Luciferase. 100 μl of Steady-Glo, aLuciferase assay substrate from Promega, is added to all wells to lysethe cells and generate luminescence in proportion to the amount ofLucifrease produced. The plates are left for a minimum of 5 minutesbefore being read on the luminescence program of a Topcount NXTmicroplate scintillation counter (ex Packard). Concentration—responsecurves are plotted from the luminescence data using Activitybasesoftware and K_(B) values for the antagonists under test are calculatedfrom the shifts of the curve at a particular concentration(K_(B)=[antagonist]/(concentration ratio−1)

[0072] Compounds of the Examples hereinbelow have K_(B) values below 300nM in the reporter gene assay. For example, the compounds of Examples12, 15, 16, 17, 27, 35, 36 and 38 have KB values of 31 nM, 20 nM, 24 nM,26.5 nM, 10 nM, 4 nM, 17 nM and 12 nM respectively.

[0073] In general, compounds of formula I in free or pharmaceuticallyacceptable salt form also exhibit inhibition of adenosine A3 receptoractivation, which may be demonstrated in the adenosine A3 receptor assaydescribed in WO 99/64418. For instance, the compounds of Examples 7, 27,30, 31, 34, 35 and 38 have K_(I) values of 24 nM, 16 nM, 22 nM, 11.5 nM,11 nM, 10 nM and 4 nM in this assay.

[0074] Having regard to their inhibition of adenosine A2b receptoractivation, and, in general, their inhibition of adnosine A3 receptoractivation, compounds of formula I in free or pharmaceuticallyacceptable salt form, hereinafter alternately referred to as agents ofthe invention, are useful in the treatment of conditions which aremediated by the activation of the adenosine A2b receptor or theadenosine A3 receptor, particularly inflammatory or allergic conditions.Treatment in accordance with the invention may be symptomatic orprophylactic.

[0075] Accordingly, agents of the invention are useful in the treatmentof inflammatory or obstructive airways diseases, resulting, for example,in reduction of tissue damage, airways inflammation, bronchialhyperreactivity, remodelling or disease progression. Inflammatory orobstructive airways diseases to which the present invention isapplicable include asthma of whatever type or genesis including bothintrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mildasthma, moderate asthma, severe asthma, bronchitic asthma,excercise-induced asthma, occupational asthma and asthma inducedfollowing bacterial infection. Treatment of asthma is also to beunderstood as embracing treatment of subjects, e.g. of less than 4 or 5years of age, exhibiting wheezing symptoms and diagnosed or diagnosableas “wheezy infants”, an established patient category of major medicalconcern and now often identified as incipient or early-phase asthmatics.(For convenience this particular asthmatic condition is referred to as“wheezy-infant syndrome”.)

[0076] Prophylactic efficacy in the treatment of asthma will beevidenced by reduced frequency or severity of symptomatic attack, e.g.of acute asthmatic or bronchoconstrictor attack, improvement in lungfunction or improved airways hyperreactivity. It may further beevidenced by reduced requirement for other, symptomatic therapy, i.e.therapy for or intended to restrict or abort symptomatic attack when itoccurs, for example anti-inflammatory (e.g. corticosteroid) orbronchodilatory. Prophylactic benefit in asthma may in particular beapparent in subjects prone to “morning dipping”. “Morning dipping” is arecognised asthmatic syndrome, common to a substantial percentage ofasthmatics and characterised by asthma attack, e.g. between the hours ofabout 4 to 6 am, i.e. at a time normally substantially distant form anypreviously administered symptomatic asthma therapy.

[0077] Other inflammatory or obstructive airways diseases and conditionsto which the present invention is applicable include acute lung injury(ALI), adult respiratory distress syndrome (ARDS), chronic obstructivepulmonary, airways or lung disease (COPD, COAD or COID), includingchronic bronchitis or dyspnea associated therewith, emphysema, as wellas exacerbation of airways hyperreactivity consequent to other drugtherapy, in particular other inhaled drug therapy. The invention is alsoapplicable to the treatment of bronchitis of whatever type or genesisincluding, e.g., acute, arachidic, catarrhal, croupus, chronic orphthinoid bronchitis. Further inflammatory or obstructive airwaysdiseases to which the present invention is applicable includepneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

[0078] Having regard to their anti-inflammatory activity, in particularin relation to inhibition of eosinophil activation, agents of theinvention are also useful in the treatment of eosinophil relateddisorders, e.g. eosinophilia, in particular eosinophil related disordersof the airways (e.g. involving morbid eosinophilic infiltration ofpulmonary tissues) including hypereosinophilia as it effects the airwaysand/or lungs as well as, for example, eosinophil-related disorders ofthe airways consequential or concomitant to Löffler's syndrome,eosinophilic pneumonia, parasitic (in particular metazoan) infestation(including tropical eosinophiiia), bronchopuimonary aspergiliosis,poiyarterltls nodosa (including Churg-Strauss syndrome), eosinophilicgranuloma and eosinophil-related disorders affecting the airwaysoccasioned by drug-reaction.

[0079] Agents of the invention are also useful in the treatment ofinflammatory or allergic conditions of the skin, for example psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, pemphisus, epidermolysis bullosa acquisita, and otherinflammatory or allergic conditions of the skin.

[0080] Agents of the invention may also be used for the treatment ofother diseases or conditions, in particular diseases or conditionshaving an inflammatory component, for example, treatment of diseases andconditions of the eye such as conjunctivitis, keratoconjunctivitissicca, and vernal conjunctivitis, diseases affecting the nose includingallergic rhinitis, and inflammatory disease in which autoimmunereactions are implicated or having an autoimmune component or aetiology,including autoimmune haematological disorders (e.g. haemolytic anaemia,aplastic anaemia, pure red cell anaemia and idiopathicthrombocytopenia), systemic lupus erythematosus, polychondritis,sclerodoma, Wegener granulamatosis, dermatomyositis, chronic activehepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue,autoimmune inflammatory bowel disease (e.g. ulcerative colitis andCrohn's disease), endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary billiary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy).

[0081] Other diseases or conditions which may be treated with agents ofthe invention include diabetes, e.g. diabetes mellitus type I (juvenilediabetes) and diabetes mellitus type II, diarrheal diseases,ischemia/reperfusion injuries, retinopathy, such as diabetic retinopathyor hyperbaric oxygen-induced retinopathy, and conditions characterisedby elevated intraocular pressure or secretion of ocular aqueous humor,such as glaucoma.

[0082] The effectiveness of an agent of the invention in inhibitinginflammatory conditions, for example in inflammatory airways diseases,may be demonstrated in an animal model, e.g. a mouse or rat model, ofairways inflammation or other inflammatory conditions, for example asdescribed by Szarka et al, J. Immunol. Methods (1997) 202:49-57 Renzi etal, Am. Rev. Respir. Dis. (1993) 148:932-939; Tsuyuki et al., J. Clin.Invest (1995) 96:2924-2931; and Cernadas et al (1999) Am. J. Respir.Cell Mol. Biol. 20:1-8.

[0083] The agents of the invention are also useful as co-therapeuticagents for use in combination with other drug substances such asanti-inflammatory, bronchodilatory or antihistamine drug substances,particularly in the treatment of obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Anagent of the invention may be mixed with the other drug substance in afixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the other drug substance.Accordingly the invention includes a combination of an agent of theinvention as hereinbefore described with an anti-inflammatory,bronchodilatory or antihistamine drug substance, said agent of theinvention and said drug substance being in the same or differentpharmaceutical composition. Such anti-inflammatory drugs includesteroids, in particular glucocorticosteroids such as budesonide,beclamethasone, fluticasone, ciclesonide or mometasone, LTB4 antagonistssuch as those described in U.S. Pat. No. 5,451,700, LTD4 antagonistssuch as montelukast and zafirlukast, dopamine receptor agonists such ascabergoline, bromocriptine, ropinirole and4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]-sulfonyl]ethyl]-amino]ethyl]-2(3H)-benzothiazoloneand pharmaceutically acceptable salts thereof (the hydrochloride beingViozan®—AstraZeneca), and PDE4 inhibitors such as Ariflo® (GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer),SCH-351591 (Schering-Plough), and PD189659 (Parke-Davis). Suchbronchodilatory drugs include anticholinergic or antimuscarinic agents,in particular ipratropium bromide, oxitropium bromide and tiotropiumbromide, and beta-2 adrenoceptor agonists such as salbutamol,terbutaline, salmeterol and, especially, formoterol and pharmaceuticallyacceptable salts thereof, and compounds (in free or salt or solvateform) of formula I of PCT International Publication No. WO00/75114,which document is incorporated herein by reference, preferably compoundsof the Examples thereof, especially a compound of formula

[0084] and pharmaceutically acceptable salts thereof. Co-therapeuticantihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride.Combinations of agents of the invention and steroids, beta-2 agonists,PDE4 inhibitors or LTD4 antagonists may be used, for example, in thetreatment of COPD or, particularly, asthma. Combinations of agents ofthe invention and anticholinergic or antimuscarinic agents, PDE4inhibitors, dopamine receptor agonists or LTB4 antagonists may be used,for example, in the treatment of asthma or, particularly, COPD.

[0085] Other useful combinations of agents of the invention withanti-inflammatory drugs are those with anatagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzocycohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770), and CCR-5 antagonists described in U.S. Pat. No.6,166,037 (particularly claims 18 and 19), WO00/66558 (particularlyclaim 8), and WO00/66559 (particularly claim 9).

[0086] In accordance with the foregoing, the invention also provides amethod for the treatment of a condition mediated by activation of theadenosine A2b receptor, and/or the adenosine A3 receptor, for example aninflammatory or allergic condition, particularly an inflammatory orobstructive airways disease, which comprises administering to a subject,particularly a human subject, in need thereof a compound of formula I infree form or in the form of a pharmaceutically acceptable salt. Inanother aspect the invention provides a compound of formula I, in freeform or in the form of a pharmaceutically acceptable salt, for use inthe manufacture of a medicament for the treatment of a conditionmediated by activation of the adenosine A2b receptor, and/or theadenosine A3 receptor, particularly an inflammatory or obstructiveairways disease.

[0087] The agents of the invention may be administered by anyappropriate route, e.g. orally, for example in the form of a tablet orcapsule; parenterally, for example intravenously; by inhalation, forexample in the treatment of inflammatory or obstructive airways disease;intranasally, for example in the treatment of allergic rhinitis;topically to the skin, for example in the treatment of atopicdermatitis; or rectally, for example in the treatment of inflammatorybowel disease.

[0088] In a further aspect, the invention also provides a pharmaceuticalcomposition comprising a compound of formula I in free form or in theform of a pharmaceutically acceptable salt, optionally together with apharmaceutically acceptable diluent or carrier therefor. The compositionmay contain a co-therapeutic agent such as an anti-inflammatory,bronchodilatory or antihistamine drug as hereinbefore described. Suchcompositions may be prepared using conventional diluents or excipientsand techniques known in the galenic art. Thus oral dosage forms mayinclude tablets and capsules. Formulations for topical administrationmay take the form of creams, ointments, gels or transdermal deliverysystems, e.g. patches. Compositions for inhalation may comprise aerosolor other atomizable formulations or dry powder formulations.

[0089] Dosages of agents of the invention employed in practising thepresent invention will of course vary depending, for example, on theparticular condition to be treated, the effect desired and the mode ofadministration. In general, suitable daily dosages for oraladministration are of the order of 0.1 to 10 mg/kg.

[0090] The invention is illustrated by the following Examples.

EXAMPLES 1-38

[0091] Compounds of formula I which are also of formula

[0092] are shown in the following table, the method of preparation beingdescribed hereinafter. The table also shows mass spectrometry (MH+)data. The Examples are in free form, with the exception of Examples 10and 25 which are in the form of salts with hydrobromic acid and Example33 which is in the form of a salt with trifluoroacetic acid. Ex R² R^(b)R¹ R² Z¹ Z² Z³ Z⁴ m/s 1 CN H

H CH N CH CH 344 2 CN H

H N CH N CH 243 3 CN H

H N CH N CH 345 4 CN H H

N CH N CH 362 5 CN H H COCH₃ N CH N CH 310 6 CN H

H N CH N CH 345 7 CN H

H N CH N CH 345 8 H Cl

H N CH N CH 355 9 CN H H

N CH N CH 402 10 CN H

H N CH N CH 359 11 CN H H

N CH N CH 336 12 CN H H

N CH N CH 402 13 CN H

H N CH N CH 373 14 CN H

H N CH N CH 359 15 CN H

H N CH N CH 359 16 CN H H

N CH N CH 392 17 CN H

H CH N CH CH 344 18 CN H

H N CH N CH 345 19 CN H H

N CH N CH 362 20 H H

H N CH N CH 320 21 H Me

H N CH N CH 334 22 CN H H

N CH N CH 350 23 CN H H

N CH N CH 373 24 CN H

H N CH N CH 373 25 CN H

H N CH N CH 369 26 CN H

H N CH N CH 375 27 CN H

H N CH N CH 346 28 F H

H N CH N CH 338 29 F H

H N CH N CH 338 30 F H

H N CH N CH 338 31 CN H

H N CH N CH 375 32 CN H

H CH N CH CH 358 33 H H

H OCH₃ N CH CH 372 34 CN H

H CH N CH CH 345 35 CN H

H OCH₃ N CH CH 360 36 CN H H

N CH N CH 376 37 CN H

H N CH N CH 377 38 CN H

H N CH N CH 420.9

PREPARATION OF SPECIFIC EXAMPLES EXAMPLE 12N-[4-(3-Cyano-phenyl)-5-[1,2,4]triazol-1-yl-thiazol-2-yl]-4-methoxy-benzamide

[0093] 4-methoxybenzoyl chloride (0.16 ml, 1.36 mmol) is added to asolution of 3-(2-amino-5-[1,2,4]triazol-1-yl-thiazol-4-yl)-benzonitrile(0.15 g, 0.56 mmol) in dry pyridine (1.5 ml). After stirring for 2 h,the reaction mixture is triturated with hot ethanol for 30 min. followedby collection of a solid by filtration. Washing the solid with ethanoland drying gives the title compound, m.s. (MH+) 402, m.p. 292-294° C.

[0094] Examples 5, 9, 11 and 22 are prepared analogously.

[0095] Starting material is prepared as follows:

[0096] 3-(2-Amino-5-[1,2,4]triazol-1-yl-thiazol-4-yl)-benzonitrile

[0097] A mixture of3-(2-bromo-2-[1,2,4]triazol-1-yl-acetyl)-benzonitrile hydrobromide(1.848 g, 5.00 mmol), thiourea (0.46 g, 1.2 mol) in ethanol is heated to95° C. for 8 h. The solvent is removed under vacuum to give a foam whichis dissolved in 3M hydrochloric acid. The product is precipitated as awhite powder by the addition of concentrated aqueous ammonia to pH 11.M.S. (MH+) 269.54.

EXAMPLE 153-[2-(6-Methyl-pyridin-2-ylamino)-5-[1,2,4]triazol-1-yl-thiazol-4-yl]-benzonitrile

[0098] 3-(2-Bromo-2-[1,2,4]triazol-1-yl-acetyl)-benzonitrilehydrobromide (500 mg, 1.34 mmol) is dissolved in ethanol (5 ml).(6-Methyl-pyridin-2-yl)-thiourea (208 mg, 1.34 mmol) is added and thereaction heated to 90° C. for 2 hours. The precipitate is collected andwashed with ethanol twice. The solid is suspended in water and basifiedwith concentrated ammonium hydroxide and the resulting precipitatecollected and washed with water to give the title compound after drying.Mass Spec (APCI+) 360.0, m.p. 236-237° C.

[0099] The thiourea starting material is prepared as follows:

[0100] (6-Methyl-pyridin-2-yl)-thiourea

[0101] 6-Methyl-pyridin-2-ylamine (1.0 g, 9.2 mmol) is dissolved inethanol (10 ml) and benzoylisothiocyanate (1.24 ml, 9.2 mmol) is addeddropwise. The mixture is heated to 40° C. with stirring for 10 minutesthen allowed to cool to room temperature. The solvent is removed invacuo and the resulting solid dissolved in 1M sodium hydroxide (15 ml)and heated under reflux for 2 hour. The resultant suspension is filteredand the solid washed copiously with water and then with cold ethanol.The solid is dried in vacuo to yield the title compound. Mass Spec(APCI+) 168.

EXAMPLE 27(3-[2-(Pyrazin-2-ylamino)-5-[1,2,4]triazol-1-yl-thiazol-4-yl]-benzonitrile):

[0102] 3-([1,2,4]Triazol-1-yl-acetyl)-benzonitrile (150 mg, 0.7 mmol) isdissolved in dioxane (640 μl) and bromine (19 μl) added dropwise. Themixture is then heated at 80° C. for 6 hours. The resultant suspensionis cooled to room temperature and the precipitate isolated byfiltration. This precipitate,3-(2-bromo-2-[1,2,4]triazol-1-yl-acetyl)-benzonitrile hydrobromide, (200mg, 0.5 mmol) is dissolved in ethanol (2 ml). Pyrazin-2-yl-thiourea (0.5mmol) is added and the reaction heated to 80° C. for 10 hours. Theethanol is removed in vacuo and the residue triturated thoroughly in 3MHCl. The resultant suspension is basified with concentrated ammoniumhydroxide and the resulting precipitate filtered and washed with waterthen cold ethanol. The solid thus obtained is dried in vacuo to give thetitle compound, m.p. >250° C., m.s. (AP+) 347.

[0103] Examples 3, 6-8, 10, 13-14, 17-18, 20-21, 24-26 and 28-31 areprepared in an analogous manner from the appropriate compounds offormulae II and III.

[0104] Starting materials are prepared as follows:

[0105] 3-([1,2,4]Triazol-1-yl-acetyl)-benzonitrile:

[0106] 3-Cyanoacetophenone (10.013 g, 69 mmol) is dissolved in dioxane(150 ml) and bromine added (3.53 ml). The mixture is stirred at roomtemperature for 30 minutes then the solvent is removed in vacuo and theresidue taken up in acetonitrile (100 ml). Sodium triazole (7 g) isadded and the mixture is stirred at room temperature overnight. Themixture is then filtered and the solid obtained discarded. The filtrateis evaporated to dryness and the solid residue taken up in 3M HCl (500ml) with heating. The aqueous layer is decanted from a gummy residue andwashed with ethyl acetate. The aqueous layer is then basified withconcentrated aqueous ammonia solution and the resultant precipitatefiltered and washed with water. This precipitate is dried in vacuo togive 3-([1,2,4]triazol-1-yl-acetyl)-benzonitrile, m.p. 172-173° C., m.s.(AP+) 213.

[0107] Other compounds of formula II are prepared in an analogous mannerfrom the appropriate acetophenone.

[0108] Pyrazin-2-yl-thiourea:

[0109] Aminopyrazine (2 g, 21.03 mmol) is dissolved in ethanol (20 ml)and benzoylisothiocyanate (2.82 ml) is added dropwise. The mixture isheated to 80° C. with stirring for 10 minutes then allowed to cool toroom temperature. The solvent is removed in vacuo and the resultingsolid dissolved in 1M sodium hydroxide (30 ml) and heated under refluxfor 1 hour. The resultant suspension is filtered and the solid washedwith water and a little cold methanol. The solid is dried in vacuo toyield the title compound, m.p. 239-239.5° C., m.s. (AP+) 138 (M+-NH₃).Other thioureas of formula III are prepared in an analogous manner fromthe appropriate starting amine.

EXAMPLE 35(3-[S-(2-Methyl-imidazol-1-yl)-2-(pyrazin-2-ylamino)-triazol-4-yl]-benzonitrile):

[0110] 3-[5-Bromo-2-(pyrazin-2-ylamino)-thiazol-4-yl]-benzonitrile (250mg, 0.698 mmol) and 2-methylimidazole (573 mg, 6.98 mmol) are combinedand heated as a melt at 150° C. for 16 h. The resulting solid ispurified by flash chromatography to yield the title compound as apowder, m.p. 276-276.5° C., m.s. 360 (TOF, ES+).

[0111] Examples 1, 2 and 32-34 are prepared in an analogous manner byreaction of the appropriate compounds of formulae IV and V.

[0112] Starting materials are prepared as follows:

[0113] 3-[2-(Pyrazin-2-ylamino)-thiazol-4-yl]-benzontrile:

[0114] 3-acetylbenzonitrile (1.0 g, 6.88 mmol) is taken up in dioxane(15 ml) and bromine (353 μl, 6.88 mmol) is added dropwise with constantstirring. The reaction is stirred for 30 minutes, then the dioxane isevaporated at reduced pressure. The resulting slurry is taken up inethanol (15 ml) and pyrazinyl-2-thiourea (1.0 g, 6.88 mmol) is added.The reaction is then heated to 80° C. for 30 minutes, cooled to roomtemperature and the ethanol distilled off at reduced pressure. The solidis suspended in 3M HCl and then basified with ammonia solution. Theresulting precipitate is filtered and washed with copious amounts ofwater and cold ethanol. Hot trituration with methanol and subsequentdrying yields the title compound, m.p. 203-204° C., m.s. 280(ES+).

[0115] 3-[5-Bromo-2-(pyrazin-2-ylamino)-thiazol-4-yl]-benzonitrile:

[0116] 3-[2-(Pyrazin-2-ylamino)-thiazol-4-yl]-benzonitrile (1.5 g, 5.36mmol) is suspended in hot glacial acetic acid (10 ml) and bromine (0.275ml) is added dropwise at room temperature with stirring. The resultantsuspension is stirred at room temperature for 10 minutes. Water (ca. 100ml) is added to the mixture, which is basified to pH 9 with solidpotassium carbonate. The resulting precipitate is filtered and washedwith water to yield3-[S-bromo-2-(pyrazin-2-ylamino)-thiazol-4-yl]-benzonitrile, m.p. 215°C. (dec.), m.s. 279 (ES+, M⁺-Br).

[0117] Other compounds of formula IV are prepared in an analogous mannerfrom the appropriate compounds of formulae IX and 1 ml.

EXAMPLE 36 1-Methyl-1H-pyrrole-2-carboxylic Acid[4-(3-cyano-phenyl)-5-[1,2,4]triazol-1-yl-thiazol-2-yl]-amide

[0118] 1-Methyl-1H-pyrrole-2-carbonyl chloride (110 mg) is added to asolution of 3-(2-amino-5-[1,2,4]triazol-1-yl-thiazol-4-yl)-benzonitrile(50 mg, 0.19 mmol) in dry pyridine (0.5 ml). After stirring for 16 h,water (10 ml) is added. After 3 days the precipitate is collected andwashed with water. The resulting cake is triturated in refluxing ethanolfor 20 min., filtered and washed with ethanol. The solid is trituratedwith saturated aqueous sodium bicarbonate, filtered, washed with waterand dried to give the title compound. Mass Spec. (MH+) 376, m.p.245-247° C.

[0119] Examples 4-5, 16, 19 and 23 are prepared analogously.

EXAMPLE 373-[2-(6-Methoxy-pyrazin-2-ylamino)-5-[1,2,4]triazol-1-yl-thiazol-4-yl]benzonitrile

[0120] 3-(2-Bromo-2-[1,2,4]triazol-1-yl-acetyl)-benzonitrilehydrobromide (250 mg, 0.67 mmol) is dissolved in ethanol (2 ml).(6-Methoxy-pyrazin-2-yl)-thiourea (0.67 mmol) is added and the reactionheated to 80° C. for 10 hours. The ethanol is removed in vacuo and theresidue triturated in 3M HCl. The resultant suspension is basified withconcentrated ammonium hydroxide and the resulting precipitate filteredand washed with water then cold ethanol. The solid thus obtained istriturated with hot ethanol and dried in vacuo to give the titlecompound. Mass Spec (APCI+) 377.1.

[0121] Example 38 is prepared analogously.

[0122] The thiourea starting material is prepared as follows:

[0123] (6-Methoxy-pyrazin-2-yl)-thiourea

[0124] 6-Methoxy-pyrazin-2-ylamine (0.85 g, 6.8 mmol) is dissolved inethanol (7 ml) and benzoylisothiocyanate (0.91 ml) is added dropwise.The mixture is heated to 80° C. with stirring for 10 minutes thenallowed to cool to room temperature. The solvent is removed in vacuo andthe resulting solid dissolved in 1M sodium hydroxide (15 ml) and heatedunder reflux for 1 hour. The resultant suspension is filtered and thesolid washed with water and a little cold ethanol. The solid is dried invacuo to yield the title compound.

EXAMPLE 39(3-[5-(2-Methyl-imidazol-1-yl)-2-(pyrazin-2-ylamino)-thiazol-4-yl]-benzontrile)methanesulfonate

[0125](3-[5-(2-Methyl-imidazol-1-yl)-2-(pyrazin-2-ylamino)-thiazol-4-yl]-benzonitrile(1 g, 2.78 mmol) is suspended in boiling pentanol (25 ml) and filteredhot to give a clear solution. Methanesulfonic acid (0.2 ml, 3.06 mmol)is added and the mixture allowed to cool to room temperature, when asolid is precipitated. Diethyl ether (25 ml) is added with stirring, andthe solid is filtered off, washed with diethyl ether and then trituratedwith diethyl ether (25 ml). The solid obtained is filtered off, dried invacuo and suspended in boiling acetone (20 ml). Water (2 ml), thenacetone (5 ml) are added and the resulting solution allowed to cool to4° C. The resulting solid is filtered off, washed with acetone and driedin vacuo at 80° C. over P₂O₅ to give the title compound, m.p. 282° C.

[0126] Starting materials are prepared as follows:

[0127] 3-(2-Methylimidazol-1-yl-acetyl)-benzonitrile

[0128] 3-acetylbenzonitrile (50 g, 0.345 mol) is dissolved in dioxane(600 ml) with stirring at room temperature, bromine (17.7 ml, 0.345 mol)is added in and the mixture is stirred for 30 minutes. The dioxane isremoved in vacuo to give a solid which is dissolved in acetonitrile (300ml). 2-Methylimidazole (28.3 g, 0.345 mol) is added to the solution andthe mixture is stirred for 1 hour, the temperature of the mixture risingto 45° C. The precipated solid is filtered off, washed withacetonitrile, and slurried with methanol for 1 hour. After filtering toremove undissolved solid, the filtrate is evaporated in vacuo to leave asolid which is dried in vacuo at 40° C. to give the title compound, m.s.369 (MH+).

[0129](3-[5-(2-Methyl-imidazol-1-yl)-2-(pyrazin-2-ylamino)-thiazol-4-yl]-benzonitrile):

[0130] 3-(2-Methylimidazol-1-yl-acetyl)-benzonitrile (13.8 g, 0.06 mol)is mixed with pyrazinyl-2-thiourea (9.4 g, 0.06 mol), iodine (15.6 g,0.06 mol) and pyridine (60 ml). The mixture is stirred, initially atroom temperature and then at 60° C. overnight (17.5 hours). The mixtureobtained is allowed to cool to room temperature and water (50 ml) added.The solid obtained is filtered off, stirred in water (50 ml) for 30minutes, and filtered off again. The resulting solid is dried at 40° C.in vacuo over P₂O₅ to give the title compound.

1. A compound of formula

in free or salt form, where Ar is a C₆-C₁₅ monovalent aromatic group, R¹is hydrogen, phenyl optionally substituted by one or more substituentsselected from halogen, cyano, hydroxy, C₁-C₈-alkyl, C₁-C₈-haloalkyl,C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl or acyloxy, or a 5- or 6-memberedmonovalent heterocyclic group, R² is hydrogen, C₁-C₈-alkyl, acyl or—CON(R³)R⁴, provided that R² is C₁-C₈-alkyl, acyl or —CON(R³)R⁴ when R¹is hydrogen, R³ and R⁴ are each independently hydrogen or C₁-C₈-alkyl,or together with the nitrogen atom to which they are attached denote a5- or 6-membered heterocyclic group, and Z¹, Z², Z³ and Z⁴ are eachindependently N or CR⁵, at least one of them being CR⁵, and R⁵ ishydrogen, C₁-C₈-alkyl or C₁-C₈-alkoxy.
 2. A compound according to claim1, in which Ar is phenyl optionally substituted by one or moresubstituents selected from halogen, cyano, C₁-C₈-alkyl orC₁-C₈-haloalkyl.
 3. A compound according to claim 1 in which Ar isphenyl optionally substituted by halogen, cyano or C₁-C₈-alkyl meta orpara to the indicated thiazole ring.
 4. A compound according to claim 1,2 or 3, in which R¹ is hydrogen, phenyl optionally substituted by cyanoor C₁-C₄-alkoxy, or a monovalent 6-membered N-heterocyclic group.
 5. Acompound according to any one of claims 1 to 4, in which R² is hydrogen,C₁-C₄-alkylcarbonyl, C₃-C₆-cycloalkylcarbonyl, phenylcarbonyl where thephenyl group is optionally substituted by C₁-C₈-alkoxy, orheterocyclylcarbonyl in which the heterocyclyl group is 5- or 6-memberedand has a ring hetero atom selected from nitrogen, oxygen and sulfur. 6.A compound according to claim 1, in which Ar is phenyl optionallysubstituted by halogen or cyano, R¹ is hydrogen, phenyl optionallysubstituted by cyano or C₁-C₄-alkoxy, or a monovalent 6-memberedN-heterocyclic group, R² is hydrogen, C₁-C₄-alkylcarbonyl,C₃-C₆-cycloalkylcarbonyl, phenylcarbonyl where the phenyl group isoptionally substituted by C₁-C₄-alkoxy, or heterocyclylcarbonyl wherethe heterocyclyl group is 5- or 6-membered and has one or two ringhetero atoms selected from nitrogen, oxygen and sulfur, and either Z¹and Z³ each denote N and Z² and Z⁴ each denote CH, or Z¹ denotes CR⁵where R⁵ is hydrogen or C₁-C₄-alkyl, Z² denotes N and Z³ and Z⁴ eachdenote CH.
 7. A compound according to claim 1, in which Ar is phenylsubstituted by halogen or cyano meta or para to the indicated thiazolering, R¹ is a monovalent 6-membered N-heterocyclic group, R² ishydrogen, and either Z¹ and Z³ each denote N and Z² and Z⁴ each denoteCH, or Z¹ denotes CR⁵ where R⁵ is hydrogen or C₁-C₄-alkyl, Z² denotes Nand Z³ and Z⁴ each denote CH.
 8. A compound according to claim 1, inwhich Ar is phenyl substituted by halogen or cyano meta or para to theindicated thiazole ring, R¹ is hydrogen, R² is phenylcarbonyl wherephenyl is optionally substituted by C₁-C₄-alkoxy, orheterocyclylcarbonyl where the heterocyclyl group is 5- or 6-memberedand has a ring hetero atom selected from oxygen and sulfur, and eitherZ¹ and Z³ each denote N and Z² and Z⁴ each denote CH, or Z¹ denotes CR⁵where R⁵ is hydrogen or C₁-C₄-alkyl, Z² denotes N and Z³ and Z⁴ eachdenote CH.
 9. A compound of formula XI XI

in free or salt form, where R^(a), R^(b), R¹, R², Z¹, Z², Z³ and Z⁴ areas shown in the following table R^(a) R^(b) R¹ R² Z¹ Z² Z³ Z⁴ CN H

H CH N CH CH CN H

H N CH N CH CN H

H N CH N CH CN H H

N CH N CH CN H H COCH₃ N CH N CH CN H

H N CH N CH CN H

H N CH N CH H Cl

H N CH N CH CN H H

N CH N CH CN H

H N CH N CH CN H H

N CH N CH CN H H

N CH N CH CN H

H N CH N CH CN H

H N CH N CH CN H

H N CH N CH CN H H

N CH N CH CN H

H CH N CH CH CN H

H N CH N CH CN H H

N CH N CH H H

H N CH N CH H Me

H N CH N CH CN H H

N CH N CH CN H H

N CH N CH CN H

H N CH N CH CN H

H N CH N CH CN H

H N CH N CH CN H

H N CH N CH F H

H N CH N CH F H

H N CH N CH F H

H N CH N CH CN H

H N CH N CH CN H

H CH N CH CH H H

H CCH₃ N CH CH CN H

H CH N CH CH CN H

H CCH₃ N CH CH CN H H

N CH N CH CN H

H N CH N CH CN H

H N CH N CH


10. A compound according to any one of the preceding claims for use as apharmaceutical.
 11. A compound according to any one of the precedingclaims in combination with an anti-inflammatory, bronchodilatory orantihistamine drug substance, said compound and said drug substancebeing in the same or different pharmaceutical composition.
 12. Apharmaceutical composition comprising as active ingredient a compoundaccording to any one of claims 1 to 11, optionally together with apharmaceutically acceptable diluent or carrier.
 13. Use of a compoundaccording to any one of claims 1 to 11 for the manufacture of amedicament for the treatment of a condition mediated by activation ofthe adenosine A2b receptor.
 14. Use of a compound according to any oneof claims 1 to 11 for the manufacture of a medicament for the treatmentof a condition mediated by activation of the adenosine A3 receptor. 15.Use of a compound according to any one of claims 1 to 11 for themanufacture of a medicament for the treatment of an inflammatory orobstructive airways disease.
 16. A method of preparing a compound offormula I in free or salt form which comprises (i) (A) for thepreparation of compounds of formula I where R¹ is optionally substitutedphenyl or a 5- or 6-membered heterocyclic group, reacting a compound offormula

 in the form of a salt, where Ar, Z¹, Z², Z³ and Z⁴ are as defined inclaim 1 and X is halogen, with a compound of formula

 where R¹ is phenyl optionally substituted by one or more substituentsselected from halogen, cyano, hydroxy, C₁-C₈-alkyl, C₁-C₈-haloalkyl,C₁-C₈-alkoxy, C₁-C₈-alkoxy-C₁-C₈-alkyl and acyloxy or R¹ is a 5- or6-membered monovalent heterocyclic group, and R² is H or C₁-C₈-alkyl or(B) for the preparation of compounds of Formula I where R¹ is optionallysubstituted phenyl or a 5- or 6-membered heterocyclic group, reacting acompound of formula

 where Ar, R¹, R² and X are as hereinbefore defined, with a compound offormula

 where Z¹, Z², Z³ and Z⁴ are as hereinbefore defined or (C) for thepreparation of compounds of formula I where R² is acyl or —CON(R³)R⁴,reacting a compound of formula

 where Ar, R¹, Z¹, Z², Z³ and Z⁴ are as defined in claim 1 with,respectively, an acylating derivative of a carboxylic acid, or with acompound of formula C₁-CON(R³)R⁴) where R³ and R⁴ are as defined inclaim 1, and (ii) recovering the resultant compound of formula I in freeor salt form.
 12. (amended) A pharmaceutical composition comprising asactive ingredient a compound according to claim 1, optionally togetherwith a pharmaceutically acceptable diluent or carrier.
 17. (new) Acompound according to claim 9, in combination with an anti-inflammatory,bronchodilatory or antihistamine drug substance, said compound and saiddrug substance being in the same or different pharmaceuticalcomposition.
 18. (new) A pharmaceutical composition comprising as activeingredient a compound according to claim 9, optionally together with apharmaceutically acceptable diluent or carrier.
 19. (new) A method oftreating a conditional mediated by activation of the adenosine A2breceptor in a subject in need of such treatment, which comprisesadministering to said subject an effective amount of a compoundaccording to claim
 1. 20. (new) A method of treating a conditionalmediated by activation of the adenosine A2b receptor in a subject inneed of such treatment, which comprises administering to said subject aneffective amount of a compound according to claim
 9. 21. (new) A methodof treating a conditional mediated by activation of the adenosine A3receptor in a subject in need of such treatment, which comprisesadministering to said subject an effective amount of a compoundaccording to claim
 1. 22. (new) A method of treating a conditionalmediated by activation of the adenosine A3 receptor in a subject in needof such treatment, which comprises administering to said subject aneffective amount of a compound according to claim
 9. 23. (new) A methodof treating an inflammatory or obstructive airways disease in a subjectin need of such treatment, which comprises administering to said subjectan effective amount of a compound according to claim
 1. 24. (new) Amethod of treating an inflammatory or obstructive airways disease in asubject in need of such treatment, which comprises administering to saidsubject an effective amount of a compound according to claim 9.